Engineering micelles with hydrophilic-lipophilic balance to overcome intestinal barrier for oral therapeutic application.

The primary challenge in developing oral nanocarriers lies in achieving a balance between mucus penetration and cellular endocytosis. Overcoming this dilemma tends to require multiple surface properties on design of nanocarriers, but it is not favorable to clinical translation due to the complex preparation procedure and availability of commercial material. Herein, we innovatively constructed a hydrophilic-lipophilic balanced micelles only composed of poly (lactic acid)-b-poly (ethylene glycol) (PLA-PEG) or poly (lactic acid)-b-poly (carboxybetaine) (PLA-PCB) for oral delivery. The hydrophobic core of micelles was reasonably exposed by adjusting the size and the molar mass ratio of hydrophilic to hydrophobic segment of polymer, and significantly enhanced cellular internalization were observed in both micelles. In addition, the hydrophobic force driven by the core of micelles was multiply confirmed as the primary factor in enhancing cellular uptake, while time-dependent endocytosis of micelles was also verified. Although the hydrophilic segment of micelles exhibited limited functionality during the adsorption-endocytosis process of micelles, their construction could significantly mediate the intracellular trafficking process. Both in vivo and ex vivo imaging suggest that micelles exhibited good retention abilities in small intestine as well as colon after gavage administration. Remarkably, the oral bioavailability of paclitaxel (PTX) in both PTX-loaded micelles exceeded 29 % and exhibited significant oral antitumor efficacy, indicating excellent potential for oral delivery via micelles. Furthermore, poly (butyric ester)-based micelles were much capable of relieving symptoms in colitis mice induced with dextran sulfate sodium salt (DSS). These results reveal that the micelles with hydrophilic-lipophilic balance possess a broad-spectrum oral therapeutic potential and are available in potential clinical practice.